This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The etiopathophysiology of schizophrenia is not completely understood. Genetic epidemiological data indicate a strong genetic component in the etiology of the illness. Several neurophysiological measures, including smooth pursuit eye movement (SPEM), evoked potentials (ERP), and functional imaging abnormalities, are shown to be related to the genetic liability of schizophrenia. For example, SPEM abnormalities are some of the most reproducible biological findings associated with the illness. Interestingly, these eyetracking abnormalities are not only observed in patients with schizophrenia, but are also found in first degree relatives of patients who do not have psychotic symptoms, suggesting that SPEM abnormalities mark a genetic liability of the illness. It has been suggested that SPEM abnormalities can serve as a phenotypic marker of schizophrenia. However, the neural basis of reported abnormalities in SPEM is not well understood, and even less is known about how genetic effects are translated into aberrant neural circuit controlling SPEM. Another example is evoked potential brain wave abnormalities, which also have been identified as potential biological markers for the genetic liability of the illness. Knowledge of the psychophysical and biological mechanisms underlying these neurophysiological phenotypes and their relationship to the schizophrenia phenotype may provide critical insight into the etiology of this disease. For this investigation we designed fMRI and event-related potential (ERP) experiments to examine the perceptual and cognitive contributions to cortical mechanisms controlling eye movement outputs. Three groups of subjects will be tested: schizophrenic patients (~ n=60), full siblings of patients (~60), and healthy controls without family history of psychosis (~60), for a total target enrollment of about 180 subjects. We expect that fMRI and ERP will provide a safe, non-invasive approach to carefully examine the neurophysiological process leading to pursuit eye movement and evoked potential dysfunction in schizophrenia in this multi-year project. We have included full siblings to examine the familial aggregation of these neurophysiological abnormalities. Since most of the siblings are not on antipsychotic medications, their inclusion allows an examination of some of the dysfunctions associated with schizophrenia in individuals not affected by antipsychotic medications. Blood DNA sample will be collected and stored in GCRC Genomic Core. We will examine candidate genes and their effects on neural imaging phenotypes. In summary, using fMRI and ERP imaging technology, we propose in this project to gain direct evidence of the abnormal circuitry controlling the candidate neurophysiological phenotypes in schizophrenia. This approach could potentially have a higher yield than behavioral measures in identifying the genetic etiology of schizophrenia because imaging techniques should be a better measure of the core biological deficits controlled by the putative disease-related genes. We should expect more robust genotype-phenotype association using imaging based phenotypes. The procedures included in this protocol, e.g., ERP recording, fMRI, or response to auditory sounds or visual motion presentations are not invasive and should pose minimal risk to research subjects.